Prescription opiate use by adolescent females has increased dramatically in the past decade. This use is highly problematic, not only due to the risks of overdose and addiction, but also due to the potential neurodevelopmental effects these drugs may have during this sensitive period. In female populations, such developmental use may also significantly impact the reproductive axis given the role that endogenous opioids play in both sexual maturation and reproductive function. By altering neural and endocrine development, short-term opiate use during adolescence could trigger long-term modifications in the female, which are then transmitted to her future offspring even in the absence of continued use. Over the past few years, we have developed an animal model of adolescent morphine exposure in female rats to examine the long-term consequences of opiate use during this unique developmental period. These studies revealed significant modifications in both gene expression and behavior in the offspring (F1 generation) of morphine exposed females. These transgenerational effects occur in the absence of in utero exposure, as all of the adolescent morphine-exposed females are drug-free for at least 21 days prior to mating. Moreover, we have recently extended our observations to the F2 generation and continue to observe effects. The nature of these modifications suggests a phenotype that may be more vulnerable to substance abuse. Interestingly, many of these effects are sex-specific. The purpose of the present proposal is to characterize the abuse potential of this phenotype using drug self-administration. Thus, we aim to characterize morphine self-administration behavior including acquisition, maintenance and reinstatement (Specific Aim 1); and compare it to cocaine self-administration acquisition, maintenance, and reinstatement (Specific Aim 2). Finally, we aim to examine the impact of both environmental enrichment and stress on the expression of this phenotype (Specific Aim 3). Studies will determine the persistence of offspring effects in the F2 generation and, by examining both male and female offspring, will also determine whether observed transgenerational effects are sexually dimorphic. Moreover, by examining two distinct drugs of abuse, we can delineate differential patterns within the reward circuitry that will provid insight into the mechanism of action of the observed phenotype. Given the increased use of opiates in this population (both medical and non-medical), understanding the persistent developmental effects of these drugs will delineate potential risks associated with opiate use beyond the direct effects on the user. We view this work in the context of intergenerational, non-genomic transfer of substance use disorders.